Zymogens and cofactors of blood coagulation

Blood coagulation is a system in which a series of zymogens of serine proteases are sequentially activated. In this regard, there is little fundamental difference between coagulation and the activation of the homologous pancreatic zymogens. There are, however, several aspects unique to coagulation which are discussed in detail. These are (1) the requirement for a high-molecular-weight protein or lipoprotein cofactor for optimal reaction rates, (2) the requirement for membranes or a membrane-like surface which further distinguishes this system; (3) a metal ion requirement for most reactions (in contrast to the pancreatic serine proteases) relating to the content of the newly described amino acid gamma-carboxyglutamic acid in the four vitamin K-dependent proteins, regarding which recent data relating to the metal binding sites on prothrombin are discussed in detail; and (4) the uniqueness of the initiating reactions in comparison to those which activate the pancreatic zymogens, insofar as no enzyme corresponding to enterokinase has been identified. The implications of this phenomenon are analyzed with particular attention to the potential role of the endogenous activity of certain zymogens in initiating coagulation. The article deals finally with the specific problems attendant on analyzing a system in which many serine proteases lacking absolute specificity are generated and regulated.